Identification of sennoside A as a novel inhibitor of the slingshot (SSH) family proteins related to cancer metastasis.

Abstract

Phospho-cofilin (p-cofilin), which has a phosphate group on Ser-3, is involved in actin polymerization. Its dephosphorylated form promotes filopodia formation and cell migration by enhancing actin depolymerization. Protein phosphatase slingshot homologs (SSHs), known as dual-specificity phosphatases, catalyze hydrolytic removal of the Ser-3 phosphate group from phospho-cofilin. Aberrant SSH activity results in cancer metastasis, implicating SSHs as potential therapeutic targets for cancer metastasis. In this study, we screened 658 natural products purified from traditional oriental medicinal plants to identify three potent SSH inhibitors with submicromolar or single-digit micromolar Ki values: gossypol, hypericin, and sennoside A. The three compounds were purified from cottonseed, Saint John's wort, and rhubarb, respectively. Sennoside A markedly increased cofilin phosphorylation in pancreatic cancer cells, leading to impaired actin dynamics in pancreatic cancer cells with or without EGF stimulation and reduced motility and invasiveness in vitro and in vivo. Collaboratively, these results demonstrate that sennoside A is a novel inhibitor of SSHs and suggest that it may be valuable in the development of pharmaceutical drugs for treating cancer metastasis.

• Authors: Seon Young Lee, Wooil Kim, Young Geun Lee, Hyo Jin Kang, Sang-Hyun Lee, Sun Young Park, Jeong-Ki Min, Sang-Rae Lee, Sang J Chung
• Journal: Pharmacological research (Pharmacol Res) Vol. 119 Pg. 422-430 (05 2017) ISSN: 1096-1186 [Electronic] Netherlands
• PMID: 28274853 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier Ltd. All rights reserved.

Chemical References

• Actin Depolymerizing Factors
• Actins
• Antineoplastic Agents
• Sennosides
• Senna Extract
• Phosphoprotein Phosphatases
• SSH1 protein, human

Topics

• Actin Depolymerizing Factors (metabolism)
• Actins (metabolism)
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Human Umbilical Vein Endothelial Cells
• Humans
• Neoplasm Invasiveness (pathology, prevention & control)
• Pancreas (drug effects, metabolism, pathology)
• Pancreatic Neoplasms (drug therapy, metabolism, pathology)
• Phosphoprotein Phosphatases (antagonists & inhibitors, metabolism)
• Phosphorylation (drug effects)
• Senna Extract (pharmacology)
• Sennosides